Short time to positivity of blood culture predicts mortality and septic shock in bacteremic patients: a systematic review and meta-analysis

Background The value of time to positivity (TTP) on diagnosis for catheter-related bloodstream infection and distinguishment on bacteria group and infection source has been investigated. However, the relationship between TTP and patient outcome requires verification, and we performed a systematic review and meta-analysis. Methods We searched PubMed, EMBASE, CINAHL, Cochrane Library, Web of Science for publications associated with the topic. We included studies that researched the TTP on predicting patient mortality and septic shock. Quality assessment is performed with Critical Appraisal Skills Programme (CASP). The analysis is performed using Review Manager Version 5.0.24. on articles available for data extraction on the exact population of each outcome group. The existence of publication bias was assessed by funnel plots. Statistical heterogeneity was evaluated using the Cochran Q and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${I}^{2}$$\end{document}I2 statistics. The outcome is reported as an odds ratio. PROSPERO registration: CRD42021272286. Results Twenty-four eligible studies were included in our study. Twenty-four in the mortality group and six in the septic shock group. Mortality is significantly associated with the short time to positivity group with an odds ratio of 2.98 (95% CI: 2.25–3.96, p-value < 0.001). The odds ratio for developing septic shock in the short TTP group is 4.06 (95% CI: 2.41–6.84, p-value < 0.001). Subgroup analysis revealed short TTP as a significant predictor of mortality and septic shock in Gram's positive and Gram's negative related bloodstream infections. TTP is not associated with mortality among patients with candidaemia. Conclusions Short time to positivity is a reliable marker for patient outcome in certain bacterial species. Studies concerning confounding factors such as the delay in bottle loading and other confounding factors are needed to enhance external validity. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-022-07098-8.


Background
Time to bacterial culture positivity, or time to positivity (TTP), is defined as the time from the start of incubation to the preliminary positive result of blood culture. The value of TTP provides indirect information of bacteremia load in the blood sample and is perceived as a new method for physicians to identify or evaluate the treatment or prognosis of the patient [1,2]. Initially, the utility of TTP is focused on recognizing the bacteria genre or infection source. TTP was then reported to be helpful with differential diagnosis of catheterrelated bloodstream infections (CRBSIs) [3], salvaging central venous catheters [4], and prognosis prediction for infective endocarditis [5]. Short TTP had also been acknowledged to be associated with mortality [5][6][7][8][9].
Though an increasing number of TTP-associated articles were published in the past decade, there is still a notable knowledge gap on the outcome prediction of TTP. Despite many articles had analyzed the correlation of TTP and patient outcome, the application of TTP requires further study. Most of the studies faced limitations such as small study populations, uncontrolled confounders, and differentiation between centers [10]. These hurdles make the implementation of TTP impractical. Thus, we aim to clarify the relationship between TTP and patient outcome, test the robustness of TTP as a predictor in patient outcome, and overcome the limitation of population size in current articles by performing a systemic review and meta-analysis.

Search strategy and study selection
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to conduct this systematic review. [11] We searched PubMed, EMBASE, CINAHL, Cochrane Library, Web of Science through August 13, 2021. The search was done with Medical Subject Headings (MeSH), and appropriate adjustments were made according to different databases. The index terms included time to positivity, time to blood culture positivity, mortality, septic shock, and prognosis, Supplementary Material Table gives the retrieval strategy in detail. We included prospective and retrospective observational studies that addressed: 1) Association of the length of TTP and patient prognosis (mortality and septic shock) or 2) Cut-off value of TTP for patient prognosis prediction. The search incorporated a limitation for articles available in English after 2000 and studies involving humans. Case reports and reviews were excluded. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO) as record number CRD42021272286.
Two authors assessed the titles and abstracts of the studies to eliminate those not relevant to the inclusion criteria. Eligible studies include those focused on patient's blood culture TTP's impact on patient outcome (mortality and septic shock). Articles discussing TTP after antibiotic usage were excluded.

Data extraction
Two independent reviewers (YC Hsieh and TC Chen) extracted the data using a standardized protocol and PICO (Patient, Intervention, Comparison, and Outcome). Disagreement on specific studies between the two reviewers was resolved through discussion or consultation with the third reviewer (SY Lin). Quality assessment is performed with the Critical Appraisal Skills Programme (CASP). The titles and abstracts were screened for relevance. After a review of the full-text articles, the following data were extracted from each study: the year of the publication, patient characteristic, study design, TTP characteristic, the proportion of death and survival in both short and long TTP groups, and the proportion of patients developing septic shock in short and long TTP groups. Short TTP and long TTP are defined through the cut-off value in each article. TTP shorter than the cut-off value defined in each study is classified into short TTP group, vice versa. The classification of septic shock was defined according to the criteria previously published in The Journal of the American Medical Association (JAMA). [12] Only articles using this criterion for septic shock were included in our analysis.

Statistical analysis
The exact number of mortality events and septic shock events in both short TTP and long TTP groups extracted from each study were combined using a Mantel-Haenszel statistical method with random-effects model, which assumes that individual studies are estimating different treatment effects, rather than the fixed-effect model, which is based on the mathematical assumption that a single common effect underlies every study in the meta-analysis. We performed the statistical analysis and subgroup analyses based on Gram's stain and Candida spp. on mortality and septic shock, respectively. In order to eradicate the bias effect contributed from the variation of cut-off value defined in each article included in the mortality group, we conducted another statistical analysis based on studies with defined TTP cut-off values shorter than the median in the mortality group, which is 12 h. Dichotomous data were reported as an odds ratio with corresponding 95% CI p-value < 0.05 is considered to be significant. Statistical heterogeneity was evaluated using the Cochran Q and I 2 statistics. ' I 2 ' denotes the percentage of total variation across the studies that are the result of heterogeneity rather than chance. We assessed for the presence of publication bias using a funnel plot. The meta-analysis was performed using Review Manager Version 5.0.24. Taiwan Nontyphoidal samonella Two sets of blood samples (10 mL each) were generally taken from separate locations, inoculated into aerobic and anaerobic culture flasks, and then incubated using the BACTEC 9240 automated detection blood culture system.
All bottles were loaded when they were received in the central laboratory. The BACTEC 9240 system continuously monitors carbon dioxide (CO2) production every 10 min, and indicates positivity by a fluorescent signal. The TTP, defined as the time from the start of incubation to the start of an alert signal, was recorded for each blood culture. When multiple cultures were positive, the shortest TTP was used for analysis

Results
The initial database search identified 230 articles. We screened titles and abstracts of a total of 145 non-duplicate records and excluded 99 articles not relevant to the topic. A total of forty-six full-text articles were reviewed for eligibility, and twenty-four studies that met our search criteria with eligible quality were included in the analysis. Twenty-four studies with complete data (twenty-four for patient mortality and six for patients developing septic shock) were included in the final meta-analysis (Table 1). All studies included in our analysis are based on bacteremia. Detailed results of our search are presented in Fig. 1 as a PRISMA flowchart.
Funnel plot analysis for the mortality group and the septic shock group showed grossly symmetrical with poor narrowing on large population studies (Figs. 7 and 8), which might represent publication bias and small sample size bias.

Discussion
In this study, we collected numerous studies about the correlation between TTP and patient outcomes. Populations on mortality and septic shock in both TTP shorter and longer than the cut-off value defined in the article were extracted if available. Meta-analysis revealed a 2.98fold higher mortality risk and a 4.06-fold higher risk for developing septic shock in the short TTP group. Subgroup analysis also showed short TTP to be an effective predictor of mortality and septic shock in different bacterial groups except for Candida species in mortality.
The utility of TTP has been investigated in several different aspects. Work has been done on the effectiveness of TTP for distinguishing bacterial species, differentiating the infection source, and predicting patient outcomes. TTP is proved to be an independent predictor of mortality and other categories of outcome in several studies [5][6][7][8][9]. Most of the previous studies reported a significant relationship between short TTP and mortality. This corresponds to the hypothesis that short TTP might be correlated to higher bacterial load [1,9,33], which results in higher mortality. Interestingly, mortality risk isn't always correlated with short TTP. In a retrospective study included in our analysis, mortality is associated with the long TTP group [8]. Six hundred eighty-four patients consisting of adult and pediatric S. aureus bacteremia revealed that TTP > 48 h was associated with higher 30-day mortality. The possible explanation might be because bacteria load in pediatric bacteremia is different in adult bacteremia, so merging two groups of S. aureus bacteremia might not be appropriate [34,35]. Three recent articles reported a non-significant relationship between TTP and mortality, but the final result of the analysis was not affected. In a cohort enrolled 87 patients with S. aureus bacteremia, TTP Fig. 2 Forest plot showing the association between short TTP and patient mortality using the random-effects model. Events, population of mortality in both TTP groups; total, total population in both TTP groups of < 12 h was not significantly associated with mortality [13]. Only patients with bacteremia persisting for more than 48 h were included, and patients who died within 48 h were excluded, which might contribute to the phenomenon. The other two studies that showed TTP to be unpredictable for mortality might be because of the small population size included in their analyses. One study of 68 patients with nontyphoidal Salmonella bacteremia [22], and another is a prospective observational study about Gram-negative bacilli bacteremia with 63 patients enrolled in the final analysis [28].
Most bacterial groups we analyzed revealed a significant relationship among the subgroup analysis of short TTP and mortality. However, our analysis reported a non-significant result (p-value = 0.7) in the Candida species group. We included two studies in Candida species subgroup analysis. One is a retrospective study including 152 patients [25]. In this article, short TTP is independently associated with an increased 6-week mortality rate in patients with candidaemia. Another is a separate cohort study including 89 adult patients with C. Albicans bacteremia infection [24]. Interestingly, this study showed that the longer the TTP, the higher the mortality Fig. 3 Forest plot showing the association between short TTP and patient mortality in Gram's stain and Candida spp. subgroups. Events, population of mortality in both TTP groups; total, total population in both TTP groups risk. The result could be the etiology of candidaemia, general patient health included in this study, or the volume inoculated into the blood culture bottles. To our knowledge, these two articles are the only articles discussing TTP and patient outcome in candidaemia and having available data for us to extract and analyze. Other articles about candidaemia and TTP mainly discuss the relationship between TTP and different Candida species or different culture sites.
The predictive capability of short TTP for septic shock events is also evaluated in our study. Our analysis revealed that short TTP could indicate septic shock, which is in line with previous studies. The result of our subgroup analysis is also consistent with previous reports.
We conducted another statistical analysis, including studies with cut-off values shorter than the median of cutoff values in our study to eradicate the effect of the varied cut-off values and the heterogenicity noticed among the articles in the mortality group. The correlation remains significant with short TTP with a higher odds ratio (3.49, 95% CI: 2.57-4.74, p-value < 0.001) compared with the original analysis (2.98, 95% CI: 2.25-3.96, p-value < 0.001) but with lower heterogenicity in the latter analysis. This result emphasizes the correlation between short TTP and mortality.
There are some limitations to our analysis. First, there might be some notable bias in our study. Although the funnel plot in our analysis is symmetrical, the narrowing is insufficient among the large population studies, which might represent possible publication bias or reporting bias. Second, heterogenicity is noted in mortality analyses. Cochrane's Q value < 0.1 and an I 2 value of 62% were noted is mortality rate analysis. This could be attributable to the variation of cut-off values in each study. Each article we included reported an individual cut-off value for TTP. Meaning every short/long TTP group is defined under different cut-off value, which could cause underlying bias and poor utility of the result of our analysis. Thus, a cut-off value would be crucial for TTP to be clinically  Forest plot showing the association between short TTP and septic shock in patients using the random-effects model. Events, population of septic shock in both TTP groups; total, total population in both TTP groups applicable, although the prediction with short TTP on patient mortality and septic shock is confirmed. However, we offset a part of the bias by performing another analysis including studies with cut-off values shorter than the median. The heterogenicity is lesser and the odds ratio is larger in this analysis. Third, merging pediatric and adult patients in our study might also contribute since children and adults have different bacterial loads and different blood culture volumes inoculated into the blood culture bottle [36,37]. Fourth, there are notable confounders in our studies. Most of them are not included in our analysis due to the small number of articles discussing the association of these factors with TTP. All of our studies did not exclude the effect of confounding factors such as the delay of bottle loading, the difference between each blood culture system, administered antimicrobials, site of infection, time to start of antimicrobials, and the volume of blood cultured [10], which might lead to hampered external validity and difficulties for TTP application in respective centers. Thus, further analyses with studies considering more confounder effects and more articles included would be necessary. Fifth, the metaregression analysis we performed revealed no significant result; this might be because of the small number of articles performing multivariate analysis with TTP and patient outcome. Last but not least, a systemic review on   if a short time to positivity is associated with high markers of inflammation is necessary for our article to prove that hyper-inflammation is the explanation of unfavorable outcomes. Only few articles discuss the correlation between inflammation marker and TTP.

Conclusion
In conclusion, this meta-analysis confirmed that a short TTP might be predictive for patient mortality and septic shock. Possible infection etiology and bacteria genre should take into concern while trying to apply this result clinically.